nKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, Hubei, China;oCenter for Human Genome Research, Huazhong University of Science and Technology, 430074 Wuhan, Hubei, China;

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Significance

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world. Several common and rare genetic risk variants associated with PD pathogenesis have been identified, predominantly in persons of European descent, but the genetic contributions to familial PD are largely unknown for Han Chinese. Here, we present a trio-based study to explore the association between de novo-altered genes and early onset PD in Han Chinese. We found that the 12 genes with de novo mutations were biologically connected to each other and likely to be disease-risk genes. Further analyses using two independent cohorts revealed that NUS1 harbored more rare nonsynonymous variants, and subsequent functional studies on Drosophila proved its potential link to PD pathogenesis.

Abstract

Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson’s disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants (P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD.

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